Morphine is a potent mu opioid receptor agonist with important central sites of action (Reisine and Pasternak, 1996). Peripheral mechanisms also have been reported and their importance is becoming increasing appreciated (Stein et al., 1995; Barber and Gottschlich, 1992; Joris et al., 1987; Junien and Wettstein, 1992). Peripheral analgesics have a number of potential advantages in the clinical treatment of pain, particularly the limitation of side-effects such as constipation and sedation which are typically seen with systemic administration. Given locally into the tail, morphine and other opioids are effective analgesics, working either alone peripherally or synergistically at central sites (Kolesnikov et al., 1996). In many respects, these studies are similar to clinical investigations (Stein, 1993; Dahl et al., 1990; Dalsgaard et al., 1994; Heard et al., 1992; Joris et al., 1987; Khoury et al., 1992; Mays et al., 1987; Raja el al., 1992). Peripheral mechanisms also have been implicated in systemic morphine tolerance (KQlesnikov et al., 1996). Early studies reported that systemic morphine tolerance does not alter the sensitivity to morphine given either spinally or supraspinally (Roerig et al., 1984). Although we also found potency to remain unchanged for spinal or supraspinal morphine following chronic morphine dosing, a profound reduction in its potency peripherally was observed (Kolesnikov et al., 1996).